Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss
2019; Cell Press; Volume: 36; Issue: 1 Linguagem: Inglês
10.1016/j.ccell.2019.05.014
ISSN1878-3686
AutoresAndrew Fedoriw, Satyajit Rajapurkar, Shane W. O’Brien, Sarah V. Gerhart, Lorna H. Mitchell, Nicholas D. Adams, Nathalie Rioux, Trupti Lingaraj, Scott Ribich, Melissa B. Pappalardi, Niyant Shah, Jenny Laraio, Yan Liu, Michael Butticello, Chris Carpenter, Caretha L. Creasy, Susan Korenchuk, Michael T. McCabe, Charles F. McHugh, Raman P. Nagarajan, Craig D. Wagner, Francesca Zappacosta, Roland S. Annan, N.O. Concha, Roberta Thomas, Timothy K. Hart, J. Joshua Smith, Robert A. Copeland, Mikel P. Moyer, John Campbell, Kim Stickland, James E. Mills, Suzanne Jacques-O’Hagan, Christina J. Allain, Danielle Johnston, Alejandra Raimondi, Margaret Porter Scott, Nigel J. Waters, Kerren K. Swinger, Ann Boriack-Sjodin, Thomas V. Riera, Gideon Shapiro, Richard Chesworth, Rabinder Prinjha, Ryan G. Kruger, Olena Barbash, Helai P. Mohammad,
Tópico(s)Cancer-related gene regulation
ResumoHighlights•GSK3368715 is a potent inhibitor of type I protein arginine methyltransferases•GSK3368715 alters exon usage and has activity against multiple cancer models•GSK3368715 synergizes with the PRMT5 inhibitor GSK3326595 to inhibit tumor growth•MTAP gene deficiency impairs PRMT5 activity, sensitizing cancer cells to GSK3368715SummaryType I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.Graphical abstract
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